A major problem in the treatment of hemophilia A patients with factor VIIII (FVIII) is that up to 30% of these patients produce antibodies to therapeutic FVIII. These antibodies block (inhibit) the pro-coagulant function of FVIII and thus are termed inhibitors. The focus of Selecta Biosciences and the Scott lab has been to develop novel approaches for the induction of tolerance so that it can be applied to the prevention or reversal of undesirable immune responses, including the formation of hemophilia inhibitors. Selecta has pioneered the use for virus-like biodegradable nanoparticles (NP) based on materials that are FDA approved, namely PLGA [poly(lactic-co-glycolic acid)] particles that have been in clinical use for more than 30 years. This nanoparticle delivery system can be used to either vaccinate or tolerize a specific immune response, focusing recently on antigen-specific immune tolerance for therapeutic and prophylactic applications. Selecta's proprietary technology platform is based on innovations in nanotechnology and immunology discovered at MIT and Harvard Medical School. In the case of hemophilia A, the delivery method involves nanoparticle delivery of FVIII (or its constituent immunodominant peptides with approved immunosuppressive drugs, such as rapamycin, in PLGA NP. Based on preliminary success with the Selecta nanoparticles with cognate antigens, as well as in our hemophilia model, we will to further this novel approach for tolerance to translation (and clinical trial). The aims of this STTR proposal are: to determine the minimal requirements for tolerance induction to FVIII with Selecta nanoparticle formulations, to further understand the mechanism of nanoparticle induced tolerance, and finally to develop evidence for human translation using an in vitro system with human dendritic cells and T cell clones. These studies should further our translation of these novel tolerogenic NP products to a clinical trial.